Pairwise genetic interactions modulate lipid plasma levels and cellular uptake
Zimon, M.; Huang, Y.; Trasta, A.; Liu, J. Z.; Chen, C.-Y.; Halavatyi, A.; Blattmann, P.; Klaus, B.; Whelan, C. D.; Sexton, D.; John, S.; Huber, W.; Tsai, E. A.; Pepperkok, R.; Runz, H.
Show abstract
Genetic interactions (GIs), the joint impact of different genes or variants on a phenotype, are foundational to the genetic architecture of complex traits. However, identifying GIs through human genetics is challenging since it necessitates very large population sizes, while findings from model systems not always translate to humans. Here, we combined exome-sequencing and genotyping in the UK Biobank with combinatorial RNA-interference (coRNAi) screening to systematically test for pairwise GIs between 30 lipid GWAS genes. Gene-based protein-truncating variant (PTV) burden analyses from 240,970 exomes revealed additive GIs for APOB with PCSK9 and LPL, respectively. Both, genetics and coRNAi identified additive GIs for 12 additional gene pairs. Overlapping non-additive GIs were detected only for TOMM40 at the APOE locus with SORT1 and NCAN. Our study identifies distinct gene pairs that modulate both, plasma and cellular lipid levels via additive and non-additive effects and nominates drug target pairs for improved lipid-lowering combination therapies.
Matching journals
The top 4 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Comprehensive genetic analysis of the human lipidome identifies novel loci controlling lipid homeostasis with links to coronary artery disease 98%
- Whole genome sequence analysis of blood lipid levels in >66,000 individuals 98%
- The genetic underpinnings of variable penetrance and expressivity of pathogenic mutations in cardiometabolic traits 96%
Similar papers in this journal
- Human gain-of-function variants in HNF1A confer protection from diabetes but independently increase hepatic secretion of multiple cardiovascular disease risk factors 95%
- Proteome-wide Mendelian randomization in global biobank meta-analysis reveals multi-ancestry drug targets for common diseases 95%
- Characterizing the genetic architecture of drug response using gene-context interaction methods 95%
Similar papers in this journal
- A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids 97%
- Rare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed Whole Genome Sequencing Study 97%
- Integration of genetic fine-mapping and multi-omics data reveals candidate effector genes for hypertension 95%
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.